Current Trends
Recommendations for the Prevention of Malaria in Travelers

Malaria continues to be an important health risk to Americans
who
travel to malaria-endemic areas of the world. The continued
extension
of chloroquine resistant Plasmodium falciparum (CRPF) in Africa,
Asia,
South America, and Oceania has reduced the number of effective
drugs
for malaria prophylaxis. In addition, some alternative drugs to
chloroquine have been found to be associated with serious adverse
reactions, and thus their usefulness is limited. Guidelines for
prophylaxis must take into account the risk of exposure to
malaria,
the effectiveness and safety of antimalarial drugs, and the use of
personal protective measures. Recommendations for the prevention
of
malaria should be revised periodically because of geographic
changes
in the occurrence of drug-resistant P. falciparum malaria, new
information on the efficacy or toxicity of drugs used for
prophylaxis,
and/or the availability of new drugs.

Malaria in humans is caused by one of four protozoan species
of
the genus Plasmodium: P. falciparum, P. vivax, P. ovale, and P.
malariae. All are transmitted by the bite of an infected female
Anopheles mosquito. Occasionally malaria is transmitted by blood
transfusion or congenitally from mother to fetus. The disease is
characterized by fever and influenza-like symptoms, which may
occur at
intervals and which include chills, headache, myalgia, and
malaise.
Malaria may be associated with anemia and jaundice, and P.
falciparum
infections may cause kidney failure, coma, and death. Deaths due
to
malaria are preventable.

Risk of Acquiring Malaria

Malaria transmission occurs in large areas of Central and
South
America, sub- Saharan Africa, the Indian Subcontinent, Southeast
Asia,* the Middle East, and Oceania. The estimated risk of
acquiring
malaria varies markedly from area to area. This variability is a
function of the intensity of transmission in both urban and rural
areas within the various regions as well as a function of the
itineraries of most travelers. For example, during the period
1983-1986, 634 cases of P. falciparum among American civilians
were
reported to CDC. Of these, 507 (80%) were acquired in sub-Saharan
Africa; 44 (7%), in Southeast Asia; and 63 (10%), in the Caribbean
and
South America. Of the 28 fatal infections, 21 were acquired in
sub-Saharan Africa. Thus, most cases of imported malaria among
American travelers were acquired in sub-Saharan Africa, despite
the
fact that only an estimated 90,000 Americans travel to sub-Saharan
Africa each year, whereas an estimated 900,000 Americans visit
Southeast Asia and South America each year. This disparity in the
risk
of acquiring malaria stems from the fact that travelers to Africa
are
at risk in most rural and many urban areas. Moreover, travelers
tend
to spend considerable amounts of time, including evening and
nighttime
hours, in rural areas where malaria risk is highest. In contrast,
most
travelers to Southeast Asia and South America spend most of their
time
in urban or resort areas where risk of exposure, if any, is
limited,
and they travel to rural areas only during daytime hours, when
risk is
limited.

Drug Resistance

Resistance of P. falciparum to chloroquine has been reported
from
all countries with P. falciparum malaria except the Dominican
Republic, Haiti, Central America, the Middle East, and the
following
countries in West Africa: Chad, Equatorial Guinea, Guinea,
Guinea-Bissau, Liberia, Senegal, and Sierra Leone. In addition,
resistance to both chloroquine and pyrimethamine/sulfadoxine
(Fansidar) is widespread in Thailand, Burma, and Kampuchea.

General Advice for Travelers to Malaria-Endemic Areas

All travelers to malaria-endemic areas are advised to use an
appropriate drug regimen and personal protection measures to
prevent
malaria. However, travelers must be informed that, regardless of
methods employed, malaria can still be contracted. Symptoms can
develop as early as 8 days after initial exposure in a
malaria-endemic
area and as late as several months after departure from a
malarious
area. Travelers should understand that malaria can be treated
effectively early in the course of the disease but that delaying
appropriate therapy can have serious or even fatal consequences.
Individuals who have the symptoms of malaria should seek prompt
medical evaluation, including thick and thin malaria smears, as
soon
as possible.

Personal Protection Measures

Because of the nocturnal feeding habits of Anopheles
mosquitoes,
malaria transmission occurs primarily between dusk and dawn.
Travelers
must be advised of the importance of measures to reduce contact
with
mosquitoes during those hours. Such measures include remaining in
well-screened areas, using mosquito nets, and wearing clothes that
cover most of the body. Additionally, travelers should be advised
to
purchase insect repellent for use on exposed skin before travel.
The
most effective repellents contain N,N diethylmetatoluamide (DEET),
an
ingredient in many commercially available insect repellents. The
actual concentration of DEET varies among repellents (ranging up
to
95%); the higher the concentration, the longer-lasting the
repellent
effect. Travelers should also be advised to purchase a
pyrethrum-containing flying-insect spray to use in living and
sleeping
areas during evening and nighttime hours.

Chemoprophylaxis

Malaria chemoprophylaxis is the use of drugs to prevent the
development of the disease. Preferably, malaria chemoprophylaxis
should begin 1-2 weeks prior to travel to malarious areas. In
addition
to assuring adequate blood levels of the drug, this regimen allows
any
potential side effects to be evaluated and treated by the
traveler's
own physician. The exception is doxycycline; because of its short
half-life, its use should begin 1-2 days before entering a
malarious
area. Chemoprophylaxis should continue during travel in malarious
areas and for 4 weeks after departure from these areas.

In choosing an appropriate chemoprophylactic regimen prior to
travel, several factors should be considered. The travel itinerary
should be reviewed in detail and compared with the information on
areas of risk within a given country to determine whether the
traveler
will actually be at risk of acquiring malaria. The risk of
acquiring
CRPF malaria is another consideration. In addition, any previous
allergic or other reaction to the antimalarial drug of choice and
the
accessibility of medical care during travel must be determined.

Chemoprophylactic Regimens

For travel to areas of risk where CRPF has not been reported
or
where only low-level or focal chloroquine resistance has been
reported, once-weekly use of chloroquine alone is recommended.
Chloroquine is usually well tolerated. The few individuals who
experience uncomfortable side effects may tolerate the drug better
by
taking it with meals or in divided, twice-weekly doses. As an
alternative, the related compound hydroxychloroquine may be better
tolerated. (See Table 1 for recommended dosages for chloroquine
and
other chemoprophylactic regimens.)

For travel to areas of risk where CRPF is endemic, once-weekly
use
of chloroquine alone is recommended. In addition, travelers to
these
areas (except those with histories of sulfonamide intolerance)
should
be given a treatment dose of Fansidar to be carried during travel
and
should be advised to take the Fansidar promptly in the event of a
febrile illness during their travel when professional medical care
is
not readily available. It must be emphasized to these travelers
that
such presumptive self-treatment of a possible malarial infection
is
only a temporary measure and that prompt medical evaluation is
imperative. They should be advised to continue their weekly
chloroquine prophylaxis after presumptive treatment with Fansidar.
(See Table 1 for recommended dosage.)

Alternative Chemoprophylactic Regimens

Doxycycline alone, taken daily, is an alternative regimen for
short-term travel to areas with risk of CRPF. It is particularly
appropriate for those individuals with a history of sulfonamide
intolerance or for those, such as short-term travelers to forested
areas of Thailand, Burma, and Kampuchea, who may be at risk in
areas
of chloroquine and Fansidar resistance. Travelers who use
doxycycline
should be cautioned about the possible side effects (see Adverse
Reactions, page 282). Doxycycline prophylaxis can begin 1-2 days
prior
to travel to malarious areas. It should be continued daily during
travel in malarious areas and for 4 weeks after departure from
these
areas.

Fansidar taken once weekly in combination with chloroquine may
be
considered in exceptional circumstances involving prolonged
exposure
in areas with intense transmission of CRPF and where medical care
is
not available. If weekly use of Fansidar is prescribed, the
traveler
should be cautioned about the possible side effects as described
in
the section on adverse reactions.

Proguanil (Paludrine) is, like pyrimethamine, a dihydrofolate
reductase (DHFR) inhibitor. Resistance of P. falciparum to DHFR
inhibitors is present in some endemic regions, but its
distribution is
not well delineated. Proguanil is not available commercially in
the
United States. Limited data suggest that it may be effective in
Kenya,
but not in Thailand and Papua New Guinea. No current data are
available on the efficacy of proguanil in other areas of CRPF,
especially West Africa. Travelers using proguanil should take a
daily
200-mg dose (adult) in combination with a weekly regimen of
chloroquine.

Mefloquine (Lariam), a new antimalarial similar in structure
to
quinine, is highly effective against both chloroquine- and
Fansidar-resistant P. falciparum infections. Approval for use in
the
United States is pending; currently the drug is available in
France
and Switzerland. Mefloquine may be considered for use by travelers
to
areas where there is risk of CRPF infection and by travelers to
areas
where P. falciparum is resistant to both chloroquine and Fansidar.
Currently available information suggests the adult prophylactic
dose
is 250 mg weekly. Mefloquine prophylaxis should begin 1 week
before
entry into the malarious area and should continue weekly while the
traveler is there. Adverse reactions are infrequent at
prophylactic
dosage but may become more common with the higher doses used in
treatment. Minor side effects observed with prophylactic doses,
such
as gastrointestinal disturbance and dizziness, tend to be
transient
and self-limited. Because mefloquine has occasionally been
associated
with asymptomatic sinus bradycardia and a prolonged QT interval,
it
should not be used by those receiving beta-blockers, calcium
channel
antagonists, or other drugs that may prolong or alter cardiac
conduction.

Primaquine: Prevention of Relapses of P. vivax and P. ovale

Unlike P. falciparum and P. malariae, P. vivax and P. ovale
have
forms that can persist in the liver and cause relapses for as long
as
4 years after routine chemoprophylaxis is discontinued. Travelers
to
malarious areas should be alerted to this risk; if they develop
malaria symptoms after they return home, they should report their
travel history and the possibility of malaria to a physician as
soon
as possible. Primaquine prevents relapses by acting against the
liver
stages of P. vivax and P. ovale; however, its use is not indicated
for
all travelers. Primaquine is administered after the traveler
leaves an
endemic area and usually in conjunction with chloroquine during
the
last 2 weeks of the 4-week period of prophylaxis after exposure in
an
endemic area has ended.

Since most malarious areas of the world (except Haiti) have at
least one species of relapsing malaria, travelers to these areas
have
some risk of acquiring either P. vivax or P. ovale. However, this
risk
is extremely difficult to quantify. Prophylaxis with primaquine is
generally indicated for persons who have had prolonged exposure in
malaria-endemic areas, e.g., missionaries and Peace Corps
volunteers.
While the actual risk to the traveler with less intense exposure
is
difficult to define, with the exception of individuals deficient
in
glucose-6-phosphate dehydrogenase (G6PD) (see Adverse Reactions,
page
282), most individuals can tolerate the standard regimen of
primaquine.

Adverse Reactions and Contraindications to Antimalarials

The frequent or serious side effects of recommended
antimalarials
are discussed below. However, physicians should review the
prescribing
information in standard pharmaceutical reference texts and in the
manufacturers' package inserts.

Chloroquine and hydroxychloroquine rarely have serious adverse
reactions when taken at prophylactic doses for malaria.
Occasionally,
minor side effects such as gastrointestinal disturbance, headache,
dizziness, blurred vision, and pruritus occur, but generally these
do
not require discontinuing the drug. While high doses of
chloroquine,
such as those used to treat rheumatoid arthritis, have been
associated
with retinopathy, this serious side effect has not been associated
with routine weekly malaria prophylaxis. However, periodic
ophthalmologic examinations for persons using chloroquine for
extended
periods (more than 6 years of cumulative weekly prophylaxis) are
recommended. Chloroquine and related compounds may exacerbate
psoriasis and may interfere with the antibody response to human
diploid cell rabies vaccine.

Amodiaquine, a 4-aminoquinoline similar to chloroquine in
structure and activity, has been used as an alternative
prophylactic
drug in areas where CRPF is endemic. It is not commercially
available
in the United States. Amodiaquine-associated agranulocytosis has
been
reported among travelers from the United Kingdom and Switzerland,
countries where the drug has been commercially available.
Therefore,
amodiaquine is not recommended for malaria prophylaxis (1).

Fansidar can cause severe adverse cutaneous reactions. Between
1982 and 1985, 24 cases of erythema multiforme, Stevens-Johnson
syndrome, and toxic epidermal necrolysis were documented among
American travelers using Fansidar. Seven of these reactions were
fatal. Available data indicate that the incidence of fatal
cutaneous
reactions associated with the use of Fansidar among American
travelers
ranges from 1/11,000 to 1/25,000 users. These severe cutaneous
reactions were associated with Fansidar when used as once-weekly
prophylaxis. Fansidar has also been associated with
serum-sickness-type reactions, urticaria, exfoliative dermatitis,
and
hepatitis. IF ONCE-WEEKLY USE OF FANSIDAR IS PRESCRIBED, THE
TRAVELER
SHOULD BE ADVISED TO DISCONTINUE IT IMMEDIATELY IF HE/SHE DEVELOPS
A
POSSIBLE ILL EFFECT, ESPECIALLY ANY SKIN OR MUCOUS MEMBRANE SIGNS
OR
SYMPTOMS, SUCH AS ITCHING, REDNESS, RASH, MOUTH OR GENITAL
LESIONS, OR
SORE THROAT. Use of Fansidar is contraindicated for persons with
histories of sulfonamide intolerance and for infants under 2
months of
age.

Doxycycline is a tetracycline and may cause side effects
associated with this group of drugs. Travelers to tropical
climates
who use doxycycline should be made aware of the possibility of
photosensitivity, usually manifested as an exaggerated sunburn
reaction. The risk of such a reaction can be minimized by avoiding
prolonged, direct exposure to the sun. In addition, doxycycline
use
may be associated with an in creased frequency of monilial
vaginitis.
Doxycycline is contraindicated in pregnancy (see Prophylaxis
During
Pregnancy, this page) and for children under 8 years of age.

Primaquine may cause severe hemolysis in G6PD-deficient
individuals. Before using primaquine, G6PD deficiency should be
ruled
out by appropriate laboratory testing.

Prophylaxis During Pregnancy

Malaria infection in pregnant women may be more severe than in
nonpregnant women. In addition, the risk of adverse pregnancy
outcomes, including prematurity, abortion, and stillbirth, may be
increased. For these reasons, and because chloroquine has not been
found to have any harmful effects on the fetus when used in the
recommended doses for malaria prophylaxis, pregnancy is not a
contraindication to malaria prophylaxis with chloroquine or
hydroxychloroquine. However, because no chemoprophylactic regimen
is
completely effective in areas with CRPF, women who are pregnant or
likely to become so should avoid travel to such areas.

The safety of Fansidar during pregnancy has not been
completely
established. Experimental data demonstrating the teratogenic
effect of
pyrimethamine in laboratory animals has resulted in restrictions
in
the licensing of compounds containing pyrimethamine. However,
pyrimethamine, alone and in combination with sulfonamides, has
been
used for nearly 30 years to treat pregnant women with toxoplas-
mosis
(another protozoal parasitic infection). While caution must be
exercised when extrapolating from accumulated case reports of
women
treated for this infection, it is difficult to implicate
pyrimethamine
as a cause of fetal abnormalities. Thus, while the teratogenic
effect
in animals cannot be ignored, published data do not substantiate
the
inference that pyrimethamine is a human teratogen.

Sulfadoxine is a sulfonamide antimicrobial that, when
administered
during the last trimester of pregnancy, theoretically could
compete
with bilirubin for plasma proteins and exacerbate neonatal
jaundice.
It is unclear, however, whether this specific sulfa congener poses
any
risk to the newborn.

Doxycycline, a tetracycline, is generally contraindicated for
malaria prophylaxis during pregnancy. Adverse effects of
tetracyclines
on the fetus include discoloration and severe dysplasia of the
teeth
and inhibition of bone growth. In pregnancy, therefore,
tetracyclines
would be indicated only if required to treat life-threatening
infections due to multidrug-resistant P. falciparum.

Primaquine should not be used during pregnancy because the
drug
may be passed transplacentally to a G6PD-deficient fetus and cause
life-threatening hemolytic anemia in utero. Whenever radical cure
or
terminal prophylaxis with primaquine is indicated, chloroquine
should
be given once a week until delivery, at which time the decision to
give primaquine may be made.

Prophylaxis While Breastfeeding

Very small amounts of antimalarial drugs are secreted in the
breast milk of lactating women. The amount of drug transferred is
not
thought to be harmful to the nursing infant; however, more
information
is needed. Because the quantity of antimalarials transferred in
breast
milk is insufficient to provide adequate protection against
malaria,
infants who require chemoprophylaxis should receive the
recommended
dosages of antimalarials (Table 1).

Chemoprophylaxis for Children

Children of any age can contract malaria. Consequently, the
indications for prophylaxis are identical to those described for
adults. Doxycycline is contraindicated for children less than 8
years
of age, and Fansidar is contraindicated for infants less than 2
months
of age.

Chloroquine phosphate, which is manufactured in the United
States
in tablet form only, tastes quite bitter. Pediatric doses should
be
calculated carefully according to body weight. Pharmacists can
pulverize tablets and prepare gelatin capsules with calculated
pediatric doses. Mixing the powder in food or drink may facilitate
the
weekly administration of chloroquine to children. Alternatively,
chloroquine in suspension is widely available overseas.

OVERDOSE OF ANTIMALARIAL DRUGS CAN BE FATAL. THE MEDICATION
SHOULD
BE STORED IN CHILDPROOF CONTAINERS OUT OF THE REACH OF CHILDREN.

Health Information for International Travel 1988 will soon be
published by the Center for Prevention Services, CDC. This
document
includes the above recommendations for the prevention and
presumptive
treatment of malaria in travelers. In addition, it includes the
chemoprophylactic regimen recommended for each country and the
risk of
malaria in each country. It will be a useful reference to health
professionals, travel agencies, international businesses, and
other
agencies that advise international travelers concerning malaria
and
other health risks they may encounter when visiting foreign
countries.
This publication will be available from the Superintendent of
Documents, U.S. Government Printing Office, Washington, D.C.
20402,
telephone (202)783-3238, as DHHS publication no. (CDC)88-8280.
Reported by: Malaria Br, Div of Parasitic Diseases, Center for
Infectious Diseases; Div of Quarantine, Center for Prevention
Svcs,
CDC.
Reference

Centers for Disease Control. Agranulocytosis associated with
the
use of amodiaquine for malaria prophylaxis. MMWR
1986;35:165-6.
*Thailand, Indonesia, Malaysia, People's Republic of China, the
Philippines, Burma, Kampuchea, Vietnam, and Laos.

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